Project Summary/Abstract: The prevalence of obesity in the developed world has reached epidemic proportions in recent years. Recently, a study examining the relationship of obesity with mortality from breast cancer found that obese women in the highest quintile of body mass index (BMI) have double the death rate from breast cancer when compared with women in the lowest quintile. In addition, in women with BMI in the highest quintile, an increased proportion of tumors were ER negative, had a high S-phase fraction, histologic grade, mitotic cell count, expression levels of proliferation markers, and a larger tumor size. These clinical observations cannot be explained only by higher estrogen levels that are associated with obesity. Importantly, independent of their menopausal status, obese breast cancer patients exhibit a higher risk for lymph node metastasis, larger tumor burden and higher mortality when compared with non-obese breast cancer patients. Thus, understanding the molecular mechanism by which obesity adversely affects the prognosis of breast cancer patients is critical in order to help devise appropriate new approaches to their treatment. Obesity affects breast carcinogenesis by autocrine and paracrine actions mediated by two major adipocytokines, leptin and adiponectin. Our recent studies investigating the oncogenic actions of leptin revealed that - i) leptin induces proliferation via Stat3 activation, ii) leptin induces invasion and migration, and iii) leptin interferes with endocrine treatment. Displaying opposing effects, adiponectin reduces invasion and migration of breast cancer cells. Adiponectin activates AMPK in an LKB1-dependent manner, and inhibits S6K activation demonstrating the involvement of LKB1-AMPK-S6K axis. Most importantly, adiponectin treatment blocks some important steps of leptin signaling. These data strongly suggest that adiponectin antagonizes the cancer-promoting effects of leptin on breast cancer cells. Our research efforts are focused on investigating the molecular mechanism by which adiponectin impedes leptin signaling and biological effects. Aiming to develop novel biomarkers to predict obesity related endocrine resistance, we will examine the important components of adiponectin and leptin signaling in clinically annotated human breast tumor samples using automated immunohistochemical analysis. Considering the high prevalence of obesity in the US, our study has the potential to significantly impact the vast majority of breast cancer patients with high leptin levels by improving their treatment response and overall survival.